Virology and Gene Therapy, and Virus-host Interactions
Accept graduate students
and postdoctoral fellows
Department of Molecular Microbiology and Immunology
Bond Life Sciences Center
University of Missouri
1201 Rollins St.
Columbia, MO 65211-7310
Tel: (573) 882-4770
Fax: (573) 884-9676
liushan [at] health [dot] missouri [dot] edu (Email)
Retroviral oncogenesis: Retroviruses have played fundamental roles in our current understanding of the molecular and genetic basis of cancer. One major focus of our lab is to better understand the novel mechanisms of cell transformation by some retroviruses. We primarily focus on two oncogenic sheep retroviruses, jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV) which cause contagious lung and nasal adenocarcinomas, respectively, in sheep and goats. JSRV transforms the type II epithelial cells of the lower airway, leading to ovine pulmonary adenocarcionoma (OPA), while ENTV transforms the epithelial cells in the nose, resulting in enzootic nasal adenocarcionoma (ENA). Distinct from most acutely transforming retroviruses, the envelope (Env) proteins of JSRV and ENTV are active oncogenes inducing malignant transformation in vitro and in vivo. More interestingly, the sheep lung tumor induced by JSRV strongly resembles human bronchiolo-alveolar carcinoma (BAC), a subclass of human pulmonary adenocarcinomas that is less associated with cigarette smoking. Hence, JSRV may provide a useful model for understanding the etiology and carciogenesis of human lung cancer.
Viral fusion and entry: We recently became interested in the fusion and entry pathways of enveloped viruses, in particular retroviruses, HCV and Ebola virus. In general viral fusion and entry into host cells takes place at the plasma membrane at neutral pH or in the intracellular compartments where an acidic pH is required. Different from most retroviruses, we find that the entry of JSRV is pH-dependent and that ENTV Env requires an even more acidic pH (pH < 4.5) for fusion activation. Intriguingly, we demonstrate that receptor binding is also required for the fusion activation of JSRV Env, possibly by triggering some initial conformation changes that prime an ultimate formation of six-helix bundles, leading to fusion. In addition, we uncovered that the N-terminal cytoplasmic tails of JSRV and ENTV Env proteins, rather than those of C-termini, inhibits membrane fusion; and this feature is quite distinct from most retroviruses, in which a C-terminal R peptide plays an inhibitory role in fusion activation. The unique mechanisms underlying the JSRV and ENTV Env-mediated fusion provide novel insights into virus entry, and have important implications for antiviral therapies.
HIV lentiviral vectors and gene therapy: The lung-specific tropism of JSRV makes it an attractive tool for lung airway gene transfer for the treatment of lung diseases, such as cystic fibrosis (CF). Unfortunately, the oncogenic potential of JSRV Env almost eliminates its possible use for human clinical trials. However, we were able to show that some modified JSRV Env mutants that do not transform cells can efficiently pseudotype the HIV-1 lentiviral vectors. Our current efforts are to find ways to increase the titers of these JSRV pseudotypes, and ultimately we will test their transduction efficacies in vivo.
XMRV biology and pathogenesis: Xenotropic murine leukemia virus-related virus (XMRV) is a recently identified gammaretrovirus that is associated with human prostate cancer and chronic fatigue syndrome. The genome structure and sequence of XMRV is very similar to other simple retroviruses found in murine and other species, and there is no identifiable oncogenes derived from the host. XMRV entry into the host cells is mediated by receptor, Xpr1, which is also shared by xenotropic and polytropic murine leukemia viruses. While the discovery of XMRV is exciting as it represents a new genuine human retrovirus, there are many questions open and to be answered. Current work in our lab focuses on the tissue tropisms of XMRV and possible mechanisms of pathogenesis, in particular its potential roles in prostate cancer and other human diseases. We are also interested in the fusion and entry pathways of XMRV, elucidation of which will have important implications for anti-XMRV therapy.
Selected Recent Publications
Côté M, Zheng YM, Liu SL. "Receptor binding and low pH coactivate oncogenic retrovirus envelope-mediated fusion" J Virol. 2009 Nov; 83(22): 11447-55.
Côté M, Zheng YM, Albritton LM, Liu SL. "Fusogenicity of Jaagsiekte sheep retrovirus envelope protein is dependent on low pH and is enhanced by cytoplasmic tail truncations." J Virol. 2008 Mar;82(5):2543-54.
Bertrand P, Côté M, Zheng YM, Albritton LM, Liu SL. "Jaagsiekte sheep retrovirus utilizes a pH-dependent endocytosis pathway for entry." J Virol. 2008 Mar;82(5):2555-9.
Côté M, Miller AD, Liu SL. "Human RON receptor tyrosine kinase induces complete epithelial-to-mesenchymal transition but causes cellular senescence." Biochem Biophys Res Commun. 2007 Aug 17;360(1):219-25.
Liu SL, Miller AD. "Oncogenic transformation by the jaagsiekte sheep retrovirus envelope protein." Oncogene. 2007 Feb 8;26(6):789-801.
Liu SL, Miller AD. "Transformation of Madin-Darby canine kidney epithelial cells by sheep retrovirus env proteins." J. Virol. 2005. 79: 927-933.
Miller AD, Van Hoeven NS, Liu SL. "Transformation and scattering activities of the receptor tyrosine kinase RON/Stk in rodent fibroblasts and lack of regulation by the jaagsiekte sheep retrovirus receptor, Hyal2." journal date and rest.
Liu SL, Halbert CL, Miller AD. "Jaagsiekte sheep retrovirus envelope efficiently pseudotypes human immunodeficiency virus type 1-based lentiviral vectors." J Virol. 2004 Mar;78(5):2642-7.
Liu SL, Lerman MI, Miller AD. "Putative phosphatidylinositol 3-kinase (PI3K) binding motifs in ovine betaretrovirus Env proteins are not essential for rodent fibroblast transformation and PI3K/Akt activation." J Virol. 2003 Jul;77(14):7924-35.
Danilkovitch-Miagkova A, Duh FM, Kuzmin I, Angeloni D, Liu SL, Miller AD, Lerman MI. "Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus." Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4580-5. Epub 2003 Apr 03.
Liu SL, Duh FM, Lerman MI, Miller AD. "Role of virus receptor Hyal2 in oncogenic transformation of rodent fibroblasts by sheep betaretrovirus env proteins." J Virol. 2003 Mar;77(5):2850-8.
Liu SL, Mittler JE, Nickle DC, Mulvania TM, Shriner D, Rodrigo AG, Kosloff B, He X, Corey L, Mullins JI. "Selection for human immunodeficiency virus type 1 recombinants in a patient with rapid progression to AIDS." J Virol. 2002 Nov;76(21):10674-84.
Liu SL, Schacker T, Musey L, Shriner D, McElrath MJ, Corey L, Mullins JI. "Divergent patterns of progression to AIDS after infection from the same source: human immunodeficiency virus type 1 evolution and antiviral responses." J Virol. 1997 Jun;71(6):4284-95.
Liu SL, Rodrigo AG, Shankarappa R, Learn GH, Hsu L, Davidov O, Zhao LP, Mullins JI. "HIV quasispecies and resampling." Science 1996 Jul 26;273(5274):415-6. No abstract available.